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Relationship: 2563

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Reduced neural crest cell migration leads to Transposition of the great arteries

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Reduced neural crest cell migration

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Transposition of the great arteries

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Inhibition of RALDH2 causes reduced all-trans retinoic acid levels, leading to transposition of the great arteries	adjacent	High	Low	Arthur Author (send email)	Open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Neural crest cells (NCCs) migrate into the pharyngeal arches 3, 4, and 6. The cardiac NCCs (cNCCs) differentiate into smooth muscle cells (SMCs) between E10.5-E13.5 in mice and between HH14-HH28 in chicken. The left fourth pharyngeal arch artery (PAA) in mammals persists and forms the segment of the aortic arch (AA) connecting the aortic sac and the descending aorta. The sixth PAA will form the pulmonary veins.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

The biological plausibility of this relationship is high. Abnormal cNCCs in mouse mutants show regression of the left fourth PAA resulting in an interrupted aortic arch (IAA) also referred to as type b interruption. cNCCs contribute to outflow tract (OFT) septation, vascular remodeling, cardiac valve formation, and possibly also to myocardial development and the conduction system (Plein et al., 2015). When comparing PAA development between taxa there is a difference in aortic arch anatomy. Avian species have a right-sided aortic arch and mammals have a left-sided aortic arch (Gittenberger-de Groot et al., 2006). The relationship between cNCCs and transposition of the great arteries became for the first time very clear in the chick-ablation model by Kirby et al. that showed a spectrum of aortic arch malformations with the fourth and sixth segments as being most vulnerable (Hutson & Kirby, 2007; Kirby, 1993; Kirby et al., 1983; Kirby & Waldo, 1995). This model was more difficult to copy in mammals, yet mouse knock-out models of endothelin 1, semaphoring 3 and Vegf164 could be traced to disturbed NCC migration and differentiation (Gittenberger-de Groot et al., 2006). As the role of cNCCs in OFT septation and aortic arch remodeling is critical in birds and mammals, this is less well understood in vertebrates (Chin et al., 2012). Zebrafish have a different circulation system as compared to mammals and e.g. don’t have a separate systemic and pulmonary circulation or an OFT septum, but they do have cNCCs. The cNCCs in zebrafish arise from a broader region of the neural tube and contributes to all cardiac regions (Chin et al., 2012; Sato et al., 2006).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Evidence for the relationship between cNCCs and transposition of the great arteries mainly resides from cNCCs ablation studies and later also from gene expression knock-out studies. Evidence for quantitative relationships is low. From the chick-ablation study specific to cNCCs, the third, fourth and sixth PAAs were targeted and showed the formation of PAAs being transformed and remodeled into the asymmetric great arteries (Kirby et al., 1983). The cNCCs differentiate into SMCs of the AA arteries for their patterning and persistence. However, they are not necessarily required for formation of these arteries (Porras & Brown, 2008). cNCC ablation in the chick model led to a malformed OFT and AA like persistent truncus arteriosus (PTA), teratology of Fallot and interrupted AA type B, overriding aorta, and ventricular septal defects (Creazzo et al., 1998; Kirby, 1993; Porras & Brown, 2008).

Studying the cNCC contribution to cardiovascular development in mammals was more difficult because of a lack of appropriate cNCC markers and it was difficult to manipulate embryonic tissue in mice (Creazzo et al., 1998). The cNCC in mammals was first mapped using a transgenic Lac-Z line (Aoto et al., 2015). Afterwards, cNCCs were studied using a Cre-Lox to lineage in Wnt1-Cre and Pax3-Cre mice (Jiang et al., 2000; Waldo et al., 1996). The heart defects that were observed in the chick ablation model as reviewed by Creazzo et al., were also found in mammals when Pax3 was knocked-out in mouse NCCs, which also resulted in alterations of connexin 43 expression in the ascending aorta (Creazzo et al., 1998; Jain et al., 2011).

Looking at AA anomalies, multiple genes related to cNCCs can be disturbed and were reviewed by Kemeda in 2009 (Kameda, 2009). Such genes involved Pax3, Alk5 (receptor of Tgfβ), Alk2 (Bmp type 1 receptor), and semaphoring 3C (Kameda, 2009). VEGF also has a role in OFT and PAA remodeling (Stalmans et al 2003). Furthermore, signaling pathways in mice such as the endothelin pathway (Clouthier et al., 1998; Kurihara et al., 1995; Morishima et al., 2003), but also mutation in TGFβ, BMP, and Smad resulted in impaired AA patterning resulted in impaired AA patterning (Molin et al., 2004; Nie et al., 2008). TGFβ2 mouse KOs also showed OFT and AA defects, and is particularly important to vascular remodeling (Kubalak et al., 2002).

Various KO genes specific to cNCCs resulted in IAA where some genes showed to affect migration and others affected subsequent development. cNCC loss of the TGFβ receptor II (Tgfbr2) showed disturbed SMC differentiation and remodeling of the OFT and PAAs in mice (Wurdak et al., 2005). However, in another NCC specific Tgfbr2 mutant study, no altered NCC specification to SMC developed, but cardiovascular malformation PTA and IAA-B did develop (Choudhary et al., 2006). Specific NCC loss of the ALK5 (TGFβ receptor) also caused PAA and OFT defects because of impaired postmigratory cNCC survival (J. Wang et al., 2006). NCC targeted deletion of Fak (focal adhesion kinase), involved in integrin, FGF, and TGFβ pathways, led to PTA, overriding aorta, ventricular septal defect, and type B interruption of the aortic arch (Vallejo-Illarramendi et al., 2009). Downstream effectors of Fak include Cdc42, Crkl, and Erk1/2 involved in cytoskeletal reorganization (Vallejo-Illarramendi et al., 2009). Cell division cycle 42 (cdc42) regulates cytoskeleton remodeling as a molecular switch and its deletion in mouse NCCs caused a halted NCC migration midway the pharyngeal arches that eventually resulted in PTA, hypomorphic pulmonary arteries, IAA and right sided aortic arches (Liu et al., 2013).

The Sem3c pathway also seems to be involved in the relationship between cNCCs and great artery formation. NCCs GATA6 inactivation results in PTA and IAA and similar inactivation in SMCs showed the same defects. These observed defects were associated with dysregulated Sem3c expression (Lepore et al., 2006).

NRP1 (SEMA3C receptor) KO in cNCCs altered migration in chicken (Toyofuku et al., 2008). Mice lacking NRP1 and NRP2 also show AA and OFT defects (Gu et al., 2003). However, proof for SEMA3C to be involved in mammalian cNCCs is lacking (Plein et al., 2015). In fact, the exact role of cNCCs in the asymmetry of vascular remodeling is not completely understood (Plein et al., 2015).

Mice with NCC specific Notch inactivation resulted in AA patterning defects, pulmonary artery stenosis, and ventricular septal defects and plays both in vitro and in vivo a role in cNCC differentiation to SMCs (High et al., 2007; Jain et al., 2010). A mutation of the gene MAML, which is under the Pax3 promotor, can block Notch signaling (Manderfield et al., 2012; Yamagishi, 2021).

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Despite the seemingly clear role of cNCCs in great artery formation, also other progenitors contribute to AAA remodeling that are in cross-talk with the cNCCs, such as the pharyngeal mesoderm and endoderm (Franco & Campione, 2003; Gittenberger-de Groot et al., 2006). Furthermore, cNCC ablation also results in altered SHF proliferation and abnormal myocardial function as secondary effects (Farrell et al., 2001; Farrell & Kirby, 2001; Leatherbury et al., 1990; Waldo et al., 2005).

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

References

List of the literature that was cited for this KER description. More help

Aoto, K., Sandell, L. L., Butler Tjaden, N. E., Yuen, K. C., Watt, K. E. N., Black, B. L., Durnin, M., & Trainor, P. A. (2015). Mef2c-F10N enhancer driven β-galactosidase (LacZ) and Cre recombinase mice facilitate analyses of gene function and lineage fate in neural crest cells. Developmental Biology, 402(1), 3–16. https://doi.org/10.1016/J.YDBIO.2015.02.022

Chin, A. J., Saint-Jeannet, J. P., & Lo, C. W. (2012). How insights from cardiovascular developmental biology have impacted the care of infants and children with congenital heart disease. Mechanisms of Development, 129(5–8), 75–97. https://doi.org/10.1016/J.MOD.2012.05.005

Choudhary, B., Ito, Y., Makita, T., Sasaki, T., Chai, Y., & Sucov, H. M. (2006). Cardiovascular malformations with normal smooth muscle differentiation in neural crest-specific type II TGFbeta receptor (Tgfbr2) mutant mice. Developmental Biology, 289(2), 420–429. https://doi.org/10.1016/J.YDBIO.2005.11.008

Clouthier, D. E., Hosoda, K., Richardson, J. A., Williams, S. C., Yanagisawa, H., Kuwaki, T., Kumada, M., Hammer, R. E., & Yanagisawai, M. (1998). Cranial and cardiac neural crest defects in endothelin-A receptor-deficient mice. Development, 125(5), 813–824. https://doi.org/10.1242/dev.125.5.813

Creazzo, T. L., Godt, R. E., Leatherbury, L., Conway, S. J., & Kirby, M. L. (1998). Role of cardiac neural crest cells in cardiovascular development. Annual Review of Physiology, 60, 267–286. https://doi.org/10.1146/annurev.physiol.60.1.267

Farrell, M. J., Burch, J. L., Wallis, K., Rowley, L., Kumiski, D., Stadt, H., Godt, R. E., Creazzo, T. L., & Kirby, M. L. (2001). FGF-8 in the ventral pharynx alters development of myocardial calcium transients after neural crest ablation. Journal of Clinical Investigation, 107(12), 1509–1517. https://doi.org/10.1172/JCI9317

Farrell, M. J., & Kirby, M. L. (2001). Cell biology of cardiac development. International Review of Cytology, 202, 99–158. https://doi.org/10.1016/S0074-7696(01)02004-6

Franco, D., & Campione, M. (2003). The role of Pitx2 during cardiac development. Linking left-right signaling and congenital heart diseases. Trends in Cardiovascular Medicine, 13(4), 157–163. https://doi.org/10.1016/S1050-1738(03)00039-2

Gittenberger-de Groot, A. C., Azhar, M., & Molin, D. G. M. (2006). Transforming growth factor beta-SMAD2 signaling and aortic arch development. Trends in Cardiovascular Medicine, 16(1), 1–6. https://doi.org/10.1016/J.TCM.2005.09.006

Gu, C., Rodriguez, E. R., Reimert, D. v., Shu, T., Fritzsch, B., Richards, L. J., Kolodkin, A. L., & Ginty, D. D. (2003). Neuropilin-1 conveys semaphorin and VEGF signaling during neural and cardiovascular development. Developmental Cell, 5(1), 45–57. https://doi.org/10.1016/S1534-5807(03)00169-2

High, F. A., Zhang, M., Proweller, A., Tu, L. L., Parmacek, M. S., Pear, W. S., & Epstein, J. A. (2007). An essential role for Notch in neural crest during cardiovascular development and smooth muscle differentiation. The Journal of Clinical Investigation, 117(2), 353–363. https://doi.org/10.1172/JCI30070

Hutson, M. R., & Kirby, M. L. (2007). Model systems for the study of heart development and disease. Cardiac neural crest and conotruncal malformations. Seminars in Cell and Developmental Biology, 18(1), 101–110. https://doi.org/10.1016/J.SEMCDB.2006.12.004

Jain, R., Engleka, K. A., Rentschler, S. L., Manderfield, L. J., Li, L., Yuan, L., & Epstein, J. A. (2011). Cardiac neural crest orchestrates remodeling and functional maturation of mouse semilunar valves. Journal of Clinical Investigation, 121(1), 422–430. https://doi.org/10.1172/JCI44244

Jain, R., Rentschler, S., & Epstein, J. A. (2010). Notch and cardiac outflow tract development. Annals of the New York Academy of Sciences, 1188, 184–190. https://doi.org/10.1111/j.1749-6632.2009.05099.x

Jiang, X., Rowitch, D. H., Soriano, P., McMahon, A. P., & Sucov, H. M. (2000). Fate of the mammalian cardiac neural crest. Development, 127(8), 1607–1616. https://doi.org/10.1242/dev.127.8.1607

Kameda, Y. (2009). Hoxa3 and signaling molecules involved in aortic arch patterning and remodeling. Cell and Tissue Research, 336(2), 165–178. https://doi.org/10.1007/S00441-009-0760-7

Kirby, M. L. (1993). Cellular and molecular contributions of the cardiac neural crest to cardiovascular development. Trends in Cardiovascular Medicine, 3(1), 18–23. https://doi.org/10.1016/1050-1738(93)90023-Y

Kirby, M. L., Gale, T. F., & Stewart, D. E. (1983). Neural crest cells contribute to normal aorticopulmonary septation. Science, 220(4601), 1059–1061. https://doi.org/10.1126/science.6844926

Kirby, M. L., & Waldo, K. L. (1995). Neural crest and cardiovascular patterning. Circulation Research, 77(2), 211–215. https://doi.org/10.1161/01.RES.77.2.211

Kubalak, S. W., Hutson, D. R., Scott, K. K., & Shannon, R. A. (2002). Elevated transforming growth factor β2 enhances apoptosis and contributes to abnormal outflow tract and aortic sac development in retinoic X receptor α knockout embryos. Development, 129(3), 733–746. https://doi.org/10.1242/dev.129.3.733

Kurihara, Y., Kurihara, H., Oda, H., Maemura, K., Nagai, R., Ishikawa, T., & Yazaki, Y. (1995). Aortic arch malformations and ventricular septal defect in mice deficient in endothelin-1. Journal of Clinical Investigation, 96(1), 293–300. https://doi.org/10.1172/JCI118033

Leatherbury, L., Gauldin, H. E., Waldo, K., & Kirby, M. L. (1990). Microcinephotography of the developing heart in neural crest-ablated chick embryos. Circulation, 81(3), 1047–1057. https://doi.org/10.1161/01.CIR.81.3.1047

Lepore, J. J., Mericko, P. A., Cheng, L., Lu, M. M., Morrisey, E. E., & Parmacek, M. S. (2006). GATA-6 regulates semaphorin 3C and is required in cardiac neural crest for cardiovascular morphogenesis. The Journal of Clinical Investigation, 116(4), 929–939. https://doi.org/10.1172/JCI27363

Liu, Y., Jin, Y., Li, J., Seto, E., Kuo, E., Yu, W., Schwartz, R. J., Blazo, M., Zhang, S. L., & Peng, X. (2013). Inactivation of Cdc42 in neural crest cells causes craniofacial and cardiovascular morphogenesis defects. Developmental Biology, 383(2), 239–252. https://doi.org/10.1016/J.YDBIO.2013.09.013

Manderfield, L. J., High, F. A., Engleka, K. A., Liu, F., Li, L., Rentschler, S., & Epstein, J. A. (2012). Notch activation of Jagged1 contributes to the assembly of the arterial wall. Circulation, 125(2), 314–323. https://doi.org/10.1161/CIRCULATIONAHA.111.047159

Molin, D. G. M., Poelmann, R. E., DeRuiter, M. C., Azhar, M., Doetschman, T., & Gittenberger-de Groot, A. C. (2004). Transforming growth factor β-SMAD2 signaling regulates aortic arch innervation and development. Circulation Research, 95(11), 1109–1117. https://doi.org/10.1161/01.RES.0000150047.16909.ab

Morishima, M., Yanagisawa, H., Yanagisawa, M., & Baldini, A. (2003). Ece1 and Tbx1 define distinct pathways to aortic arch morphogenesis. Developmental Dynamics : An Official Publication of the American Association of Anatomists, 228(1), 95–104. https://doi.org/10.1002/DVDY.10358

Nie, X., Deng, C. xia, Wang, Q., & Jiao, K. (2008). Disruption of Smad4 in neural crest cells leads to mid-gestation death with pharyngeal arch, craniofacial and cardiac defects. Developmental Biology, 316(2), 417–430. https://doi.org/10.1016/J.YDBIO.2008.02.006

Plein, A., Fantin, A., & Ruhrberg, C. (2015). Neural crest cells in cardiovascular development. In Current Topics in Developmental Biology (1st ed., Vol. 111). Elsevier Inc. https://doi.org/10.1016/bs.ctdb.2014.11.006

Porras, D., & Brown, C. B. (2008). Temporal-spatial ablation of neural crest in the mouse results in cardiovascular defects. Developmental Dynamics : An Official Publication of the American Association of Anatomists, 237(1), 153–162. https://doi.org/10.1002/DVDY.21382

Sato, M., Tsai, H. J., & Yost, H. J. (2006). Semaphorin3D regulates invasion of cardiac neural crest cells into the primary heart field. Developmental Biology, 298(1), 12–21. https://doi.org/10.1016/J.YDBIO.2006.05.033

Toyofuku, T., Yoshida, J., Sugimoto, T., Yamamoto, M., Makino, N., Takamatsu, H., Takegahara, N., Suto, F., Hori, M., Fujisawa, H., Kumanogoh, A., & Kikutani, H. (2008). Repulsive and attractive semaphorins cooperate to direct the navigation of cardiac neural crest cells. Developmental Biology, 321(1), 251–262. https://doi.org/10.1016/j.ydbio.2008.06.028

Vallejo-Illarramendi, A., Zang, K., & Reichardt, L. F. (2009). Focal adhesion kinase is required for neural crest cell morphogenesis during mouse cardiovascular development. The Journal of Clinical Investigation, 119(8), 2218–2230. https://doi.org/10.1172/JCI38194

Waldo, K. L., Hutson, M. R., Stadt, H. A., Zdanowicz, M., Zdanowicz, J., & Kirby, M. L. (2005). Cardiac neural crest is necessary for normal addition of the myocardium to the arterial pole from the secondary heart field. Developmental Biology, 281(1), 66–77. https://doi.org/10.1016/J.YDBIO.2005.02.011

Waldo, K. L., Kumiski, D., & Kirby, M. L. (1996). Cardiac neural crest is essential for the persistence rather than the formation of an arch artery. Developmental Dynamics, 205(3), 281–292. https://doi.org/10.1002/(SICI)1097-0177(199603)205:3<281::AID-AJA8>3.0.CO;2-E

Wang, J., Nagy, A., Larsson, J., Dudas, M., Sucov, H. M., & Kaartinen, V. (2006). Defective ALK5 signaling in the neural crest leads to increased postmigratory neural crest cell apoptosis and severe outflow tract defects. BMC Developmental Biology, 6. https://doi.org/10.1186/1471-213X-6-51

Wurdak, H., Ittner, L. M., Lang, K. S., Leveen, P., Suter, U., Fischer, J. A., Karlsson, S., Born, W., & Sommer, L. (2005). Inactivation of TGFβ signaling in neural crest stem cells leads to multiple defects reminiscent of DiGeorge syndrome. Genes and Development, 19(5), 530–535. https://doi.org/10.1101/gad.317405

Yamagishi, H. (2021). Cardiac neural crest. Cold Spring Harbor Perspectives in Biology, 13(1), 1–18. https://doi.org/10.1101/CSHPERSPECT.A036715